Volume 26, Issue 7 (10-2019)                   RJMS 2019, 26(7): 33-56 | Back to browse issues page

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jahanbani A, Ajjadi Dezfouli M. Review of artificial aspartame sweetener. RJMS 2019; 26 (7) :33-56
URL: http://rjms.iums.ac.ir/article-1-5411-en.html
PhD Student, Department of Biochemistry, Vetrinary School, Shiraz University, Shiraz, Iran , ajahanbani@shirazu.ac.ir
Abstract:   (5062 Views)
Aspartame as a synthetic sweetener is a dipeptide composed of aspartic acid and phenylalanine. It is 180 -200 times more sweetener than sucrose, which is made by two enzymatic and non-enzymatic methods and was first discovered randomly in 1965. The high sweetening power and low calorie of aspartame was prompted food industry that it used as a good alternative compared to sugar in sweet foods such as all types of beverages and sweets for people with diseases that associated with glucose homeostasis.
In several years ago, some studies have shown that aspartame has been considered as a reason for induction of oxidative stress, metabolic syndrome, nervous system diseases, modifier of gastrointestinal microflora, and complications that related to these and even cancer. While, in the other studies, aspartame is still considered as a safe compound and an alternative compared to sugar for prevention of diseases such as obesity, diabetes and weight loss.
Despite of contradictory studies, food safety organizations such as the FDA, the FAO, and the EFSA, are still authorizing daily use of aspartame at an acceptable daily intake (DAI) for all individuals with the exception of people with phenylctonuria disease.
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Type of Study: review article | Subject: Biochemistry

1. 1. Aspartame: National Center for Biotechnology Information. (https://pubchem.ncbi.nlm.nih.gov/compound/aspartame.) 28 March 2018.
2. 2. EU Food Improvement Agents. Aspartame: (http://data.europa.eu/eli/reg/2012/231/oj) 28 March 2018.
3. 3. Rycerz K, Jaworska-Adamu JE .Effects of aspartame metabolites on astrocytes and neurons. Folia Neuropathol; 2013. 51(1):10-17.
4. 4. Chem I Dplus. Aspartame: (https://chem.nlm.nih.gov/chemidplus/sid/0022839470) 29 March 2018.
5. 5. Gougeon R, Spidel M, Lee K, Field CJ. Canadian Diabetes Association National Nutrition Committee Technical Review: non-nutritive intense sweeteners in diabetes management. Can J Diabetes; 2004.28:385–399.
6. 6. Joint Expert Committee on Food Additives.Aspartame.
7. 7. http://www.inchem.org/documents/jecfa/jeceval/jec_165.htm) 11 Mar 2003.
8. 8. European Food Safety Authority (EFSA).AsPartame/E951. (https://www.efsa.europa.eu/en.) 29 March 2018.
9. 9. Murakami Y, Hirata M, Hirata A. Mathematical approach to thermolysin-catalyzed synthesis of aspartame precursor. Journal of fermentation and bioengineering;1996 . 82(3):246-52.
10. 10. Paul F, Auriol D, Monsan P. Direct Enzymatic Synthesis of Aspartamea. Enzyme Engineering; 1988: 542 (1): 351-355.
11. 11. Tsuchiyama S, Doukyu N, Yasuda M, Ishimi K , Ogino H. Peptide Synthesis of Aspartame Precursor Using Organic‐Solvent‐Stable PST‐01 Protease in Monophasic Aqueous‐Organic Solvent Systems. Biotechnology Progress;2007: 23(4): 820-823.
12. 12. Tang XY, Wu B,Ying HJ, He BP. Biochemical Properties and Potential Applications of a Solvent-Stable Protease from the High-Yield Protease Producer Pseudomonas aeruginosa PT121. Appl Biochem Biotechnol; 2010. 160:1017–1031.
13. 13. Furukawa S, Hasegawa K, Fuke I, Kittaka K, Nakakoba T, Goto M, Kamiya N. Enzymatic synthesis of Z-aspartame in liquefied amino acid
14. substrates. Biochem Engineer J; 2013 15:70:84-7.
15. 14. Yang CP, Su CS. Effects of solvents and additives on the reaction of N-(benzyloxycarbonyl)-L-aspartic anhydride with L-phenylalanine methyl ester (synthesis of aspartame). The Journal of Organic Chemistry;1986.51(26):5186-91.
16. 15. Declerck V, Nun P, Martinez J, Lamaty F. Solvent-Free Synthesis of Peptides. Angew Chem Int; 2009. 48: 9318 –9321.
17. 16. Stephen L. Burgert, Dean W. Andersen, Lewis D. Stegink, Hisanao Takeuchi, and Harold P. Schedl. Metabolism of Aspartame and Its L-Phenylalanine Methyl Ester Decomposition Product by the Porcine Gut. Metabolism; 1991.40(6): 612-618.
18. 17. Information in the package leaflet for aspartame in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’ (CPMP/463/00 Rev. 1) EMA/CHMP/134648/2015. Available at: https://www.ema.europa.eu/en/ documents/scientific-guideline/draft-information-package-leaflet-aspartame-context-revision-guideline-excipients-label-package/463/00-rev-1_en.pdf
19. 18. Tobey NA, Heizer WD. Intestinal hydrolysis of aspartylphenylalanine -The metabolic product of aspartame. Gastroenterology; 1986.91(4):931-7.
20. 19. Stephen L. Burgert, Dean W. Andersen, Lewis D. Stegink, Hisanao Takeuchi, and Harold P. Schedl. Metabolism of Aspartame and Its L-Phenylalanine Methyl Ester Decomposition Product by the Porcine Gut. Metabolism; 1991. 40(6): 612-618.
21. 20. Humphries P, Pretorius E, Naude H. Direct and indirect cellular effects of aspartame on the brain. European Journal of Clinical Nutrition; 2008.62: 451–462. Available at: https://www.nature.com/ articles/1602866
22. 21. http://www.robertbarrington.net/s=aspartame.26 April 2018.
23. 22. 21- Horton V L, Higuchi M A, Rickert D E. Physiologically based pharmacokinetic model for methanol in rats, monkeys, and humans. Toxicology and Applied Pharmacology; 1992.117(1):26-36.
24. 23. Barceloux DG, Randall Bond G, Krenzelok EP, Cooper H, Allister Vale J. American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. Journal of Toxicology: Clinical Toxicology; 2002.40(4):415-46.
25. 24. Palese M, Tephly T R. Metabolism of formate in the rat. Journal of Toxicology and Environmental Health; 2009.1(1): 13-24.
26. 25. Filer LJ, Stegink LD. Aspartame Metabolism in Normal Adults, Phenylketonuric Heterozygotes, and Diabetic Subjects. Diabetes Care; 1989. 12(1):67-74.
27. 26. Stephen L. Burgert, Dean W. Andersen, Lewis D. Stegink, Hisanao Takeuchi, and Harold P. Schedl. Metabolism of Aspartame and Its L-Phenylalanine Methyl Ester Decomposition Product by the Porcine Gut. Metabolism; 1991.40(6): 612-618.
28. 27. Ranney RE, Oppermann JA, Muldoon E, McMahon F. Comparative metabolism of aspartame in experimental animals and humans. Journal of Toxicology and Environmental Health; 1976. 2:441-451.
29. 28. Robert K. Murray, David A Bender, Kathleen M. Botham, Peter J. Kennelly, Victor W. Rodwell, P. Anthony Weil. Harper's Illustrated Biochemistry; 2015. Chapter 29, 30th ed. USA: The McGraw-Hill Companies.
30. 29. Hjelle JJ, Dudley RE, Marietta MP, Sanders PG, Dickie BC, Brisson J, Kotsonis FN. Plasma concentrations and pharmacokinetics of phenylalanine in rats and mice administered aspartame. Pharmacology; 1992.44(1):48-60.
31. 30. Butchko HH, Stargel WW, Comer CP, Mayhew DA, Benninger C, Blackburn GL, de Sonneville LM, Geha RS, Hertelendy Z, Koestner A, Leon AS. Aspartame: review of safety. Regulatory Toxicology and Pharmacology; 2002 Apr 1. 35(2):S1-93.
32. 31. An Approach to Defining the Upper Safe Limits of Amino Acid Intake J Nutr. J Nutr | © 2008 American Society for Nutrition; 2008.138(10):1996S-2002S
33. 32. Thomas M. Devlin. Textbook of Biochemistry with Clinical Correlations, 7th ed. New York, USA: Wiley-Liss, Inc; 2011.
34. 33. Palmnäs MS, Cowan TE, Bomhof MR, Su J, Reimer RA, Vogel HJ, et al. Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat. PloS One; 2014.9(10):e109841.
35. 34. European Commission. Health and Consumer Protection Directorate-General, Scientific Committee on Food. Opinion of the scientific committee on food: update on the safety of aspartame. SCF; 2002. December 2002. http://europa.eu.int/comm/food/fs/sc/scf/index_en.html
36. 35. Stegink L D. Filer J, George Jr, Baker L. Plasma, Erythrocyte and Human Milk Levels of Free Amino Acids in Lactating Women Administered Aspartame or Lactose. J Nutr; 1979. 109(12): 2173–2181.
37. 36. Onaolapo A Y, Onaolapo O J, Nwohac P N. Alterations in behaviour, cerebral cortical morphology and cerebral oxidative stress markers following aspartame ingestion. Journal of Chemical Neuroanatomy; 2016.78(1): 42-56.
38. 37. Amchra FZ., Chaouqi S, Khiraoui A, Benhmimou A. Effect of Stevia rebaudiana, sucrose and aspartame on human health: A comprehensive review. JMPS; 2018. 6(1): 102-108.
39. 38. Ashok L, Sheeladev R. Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain. Redox Biology; 2014.
40. 39. Rycerz K, Jaworska-Adamu JE. Effects of aspartame metabolites on astrocytes and neurons. Folia Neuropathol; 2013. 51(1):10-17.
41. 40. Baothman O, Moselhy SS, Al-Shehri SH, AL-Malki AL. Impact of Aspartame Consumption on Neurotransmitters in Rat Brain. Afr J Tradit Complement Altern Med; 2017.14 (5): 89-95.
42. 41. Abhilash M, Alex M, Mathews VV, Nair RH. Chronic Effect of Aspartame on Ionic Homeostasis and Monoamine Neurotransmitters in the Rat Brain.Int J Toxicol; 2014. 33(4):332-341.
43. 42. Saleh AB. Synergistic effect of N-acetyl cysteine and folic acid against aspartame- induced nephrotoxicity in rats. International Journal of Advanced Research; 2014. 2(5): 363-373.
44. 43. Tootian Z, Limouei H, Sheibani MT, Fazelipour S, SalarAmoli J. Morphometrical and histometrical changes of kidney in immature mice exposed to aspartame. Journal of Veterinary Research; 2013.68(2):159-165. (Persian)
45. 44. Finamor I. N-acetylcysteine protects the rat kidney against aspartame-induced oxidative stress. Free Radical Biology and Medicine; 2014.75:S30.
46. 45. Butchko HH, Stargel WW, Comer CP, Mayhew DA, Benninger C, Blackburn GL, de Sonneville LM, Geha RS, Hertelendy Z, Koestner A, Leon AS. Aspartame: review of safety. Regulatory Toxicology and Pharmacology; 2002.35(2):S1-93.
47. 46. Finamor I, Pérez S, Bressan CA, Brenner CE, Rius-Pérez S, Brittes PC, Cheiran G, Rocha MI, da Veiga M, Sastre J, Pavanato MA. Chronic aspartame intake causes changes in the trans-sulphuration pathway, glutathione depletion and liver damage in mice. Redox biology; 2017. 1(11):701-7.
48. 47. Iyaswamy A, Rathinasamy S. Oxidant stress evoked damage in rat hepatocyte leading to triggered nitric oxide synthase (NOS) levels on long term consumption of aspartame. JFDA; 2015.23(4):679-691.
49. 48. Iyaswamy A, Kammella AK, Thavasimuthu C, Wankupar W, Dapkupar W, Shanmugam S, et al. Oxidative stress evoked damages leading to attenuated memory and inhibition of NMDAR–CaMKII–ERK/CREB signalling on consumption of aspartame in rat model. JFDA; 2018.26(2):903-16.
50. 49. William N, Fares N, Nimer A. Soft drinks consumption and nonalcoholic fatty liver disease. World Journal of Gastroenterology; 2010.16(21): 2579-2588.
51. 50. Kamenickova A, Pecova M, Bachleda P, Dvorak Z. Effects of artificial sweeteners on the AhR- and GR-dependent CYP1A1 expression in primary human hepatocytes and human cancer cells. Toxicology in Vitro; 2013. 27(8):2283–2288.
52. 51. Higgins K, Considine R, Mattes RD. Aspartame Consumption for 12 Weeks Does Not Affect Glycemia, Appetite, or Body Weight of Healthy, Lean Adults in a Randomized Controlled Trial. The Journal of Nutrition; 2018.148(4):650–657.
53. 52. International Diabetes Association: )http://www.international-diabetes-association.com/ metabolic-syndrome; 2015.14 July.
54. 53. Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature; 2014.514(7521):181.
55. 54. Polyák É, Gombos K, Hajnal B, Bonyár-Müller K, Szabó S, Gubicskó-Kisbenedek A, et al. Effects of artificial sweeteners on body weight, food and drink intake. Acta Physiologica Hungarica; 2010.97(4):401-7.
56. 55. Collison KS, Makhoul NJ, Zaidi MZ, Al-Rabiah R, Inglis A, Andres BL, et al. Interactive effects of neonatal exposure to monosodium glutamate and aspartame on glucose homeostasis. Nutr Metabol; 2012. 9(1):58.
57. 56. Rabena A, Richelsen B. Artificial sweeteners: a place in the field of functional foods? Focus on obesity and related metabolic disorders. FFDS; 2012.15(6):597-604.
58. 57. Swither S. Artificial sweeteners are not the answer to childhood obesity. Appetite; 2015.93:85-90.
59. 58. Rahiman F, Pool EJ. The in vitro effects of artificial and natural sweeteners on the immune system using whole blood culture assays. J Immunoass Immunochem; 2014.35(1):26-36.
60. 59. Choudhary AK, Devi RS. Effects of aspartame on hsp70, bcl-2 and bax expression in immune organs of Wistar albino rats. The Journal of Biomedical Research ; 2016.30(5):427–435.
61. 60. Hardcastle JE, Bruch RJ. Effect of L.aspartyI.L.phenylalanine methyl ester on leukotriene biosynthesis in macrophage cells. PLEFA; 1997.57(3): 331-333.
62. 61. Szucs EF, Barrett KE, Metcalfe DD. The effects of aspartame on mast cells and basophils. Food and chemical toxicology; 1986.24(2):171-4.
63. 62. Ramsland P A, Movafagh B F, Reichlin M, Edmundson A B. Interference of rheumatoid factor activity by aspartame, a dipeptide methyl ester. Journal of Molecular Recognition; 1999.12(5):249-257.
64. 63. Poussin C, Sierro N, Boué S, Battey J, Scotti E, Belcastro V, et al. Interrogating the microbiome: experimental and computational considerations in support of study reproducibility. Drug discovery today; 2018.8.
65. 64. Cowan TE, Palmnäs MS, Yang J, Bomhof MR, Ardell KL, Reimer RA, et al. Chronic coffee consumption in the diet-induced obese rat: impact on gut microbiota and serum metabolomics. The Journal of nutritional biochemistry; 2014.25(4):489-95.
66. 65. Kashanian S, Mohmmad Mehdi Khodaei M, Kheirdoosh F. In vitro DNA binding studies of Aspartame, an artificial sweetener. Journal of Photochemistry and Photobiology Biology; 2013.120:104–110.
67. 66. Kirkland D, Gatehouse D. Aspartame: A review of genotoxicity data. Food and Chemical Toxicology; 2015.84:161-168.
68. 67. U S Food and Drug Administration . Aspartam. (https://www.fda.gov/food/ingredientspackaginglabeling/foodadditivesingredients/ucm208580.htm) 4 May 2018.
69. 68. Soffritti M, Padovani M, Tibaldi E, Falcioni L, Manservisi F, Belpoggi F. The Carcinogenic Effects of Aspartame: The Urgent Need for Regulatory Re-Evaluation. American Journal of Industrial Medicine; 2014.57(4):383–397.
70. 69. Lohner S, Toews I, Meerpohl J. Health outcomes of non-nutritive sweeteners: analysis of the research landscape. Nutrition Journal; 2017.16.
71. 70. Haighton L, Roberts A, Walters B, Lynch B. Systematic review and evaluation of aspartame carcinogenicity bioassays using quality criteria. Regulatory Toxicology and Pharmacology; 2018.
72. 71. Dooley J, Lagou V, T Dresselaers T , Katinka A. Dongen V, Himmelreich U , et al . No Effect of Dietary Aspartame or Stevia on Pancreatic Acinar Carcinoma Development, Growth, or Induced Mortality in a Murine Model. Frontiers in Oncology; 2017.7 (February 2017).
73. 72. Pandurangan M, Enkhtaivan G, Mistry B, Chandrasekaran M, Noorzai R, Kim D. Investigation of role of aspartame on apoptosis process in HeLa cells. Saudi Journal of Biological Sciences; 2016.23(4): 503–506.
74. 73. Soffritti F, Belpoggi F, Esposti D, Lambertini L, Tibaldi E, Rigano A. First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats. Environmental Health Perspectives ;2006.114(3):379-385.
75. 74. Soffritti M, Belpoggi F, Tibaldi E, Esposti D, Lauriola M . Life-Span Exposure to Low Doses of Aspartame Beginning during Prenatal Life Increases Cancer Effects in Rats. Environmental Health Perspectives; 2007.115(9):1293-1297.
76. 75. Yılmaz S, Ucar A. A review of the genotoxic and carcinogenic effects of aspartame: does it safe or not? Cytotechnology; 2014. 66(February 2014):875–881.
77. 76. Zafar T, Naik QAB, Shrivastava VK. Aspartame: Effects and Awareness. MOJ Toxicol; 2017. 3(2).
78. 77. Ardalan MR, Tabib H, Ebrahimzadeh Attari V, Malek Mahdav I . Nephrotoxic Effect of Aspartame as an Artificial Sweetener. Iranian Journal of Kidney Diseases; 2017.11:339-343.
79. 78. Aune D. Soft drinks, aspartame, and the risk of cancer and cardiovascular disease.American Journal of Clinical Nutrition; 2012. 96(6):1249–51.
80. 79. Azad MB, Abou-Setta AM, Chauhan BF, Rabbani R, Lys J, Copstein L, et al. Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. CMAJ; 2017.189(28):E929-39.

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